Ignite Creation Date:
2024-05-06 @ 12:27 AM
Last Modification Date:
2024-10-26 @ 10:50 AM
Study NCT ID:
NCT01581424
Status:
RECRUITING
Last Update Posted:
2023-10-04
First Post:
2012-01-17
Brief Title:
Natural History and Structural Functional Relationships in Fabry Renal Disease Treatment OutcomesChangesin Fabry Renal Disease Study
Sponsor:
University of Minnesota
Organization:
University of Minnesota
Study Overview
Official Title:
Natural History and Structural Functional Relationships in Fabry Renal Disease Natural History Structural Functional Relationships and Determinants of Renal Structural Responses Changes With Enzyme Replacement Therapy in Fabry Disease
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
LDN6702
Brief Summary:
The investigators will perform a study with two major components The first is a natural history study of untreated Fabry patients This study component will detail kidney microscopic structural changes in Fabry patients before starting enzyme replacement therapy and will correlate these changes with kidney function including glomerular filtration rate and urinary albumin excretion rate The investigators will perform studies on samples obtained at baseline or before enzyme replacement therapy is initiated The goal of our study is to find kidney microscopic changes in the biopsies that are associated with kidney disfunction Our hypotheses for this study are
1 Much of the natural history of Fabry renal structural changes will occur without detectable renal functional alterations
2 Structural changes associated with the initial onset of proteinuria and those associated with the subsequent progressive loss of filtration function will differ and will be best described by non-linear models
3 There will be sufficient precision of Fabry renal structural-functional relationships to support renal structure as an acceptable clinical trial surrogate endpoint for later renal functional deterioration
The second component examines the effects of age and gender at start of enzyme replacement therapy ERT as well as dosage levels of ERT on the renal cellular clearance of GL3 from Fabry patients by comparing baseline to follow-up kidney biopsies performed 5 11 and 60 months later with all comparisons matched for ERT treatment duration Our hypotheses for this component of the study are as follows
1 Enzyme Replacement TherapyERT instituted at younger ages is more effective in reducing podocytesPCdistal tubular cellsDTCand arterial smooth muscle cells ASMCGL-3 than in older Fabry patients
2 Earlier institution of ERT will stabilize PC numbers while later ERT institution especially in proteinuric adults may not prevent progressive decline in PC numbers and associated glomerular sclerosis tubulointerstitial injury and GFR loss
3 Whereas lower ERT dose may effectively clear GL-3 from endothelial and mesangial cells it will be less effective in clearing GL-3 from PC and also from DTC and ASMC
4 Affected cells will be cleared of GL-3 equivalently in females and males
1 Much of the natural history of Fabry renal structural changes will occur without detectable renal functional alterations
2 Structural changes associated with the initial onset of proteinuria and those associated with the subsequent progressive loss of filtration function will differ and will be best described by non-linear models
3 There will be sufficient precision of Fabry renal structural-functional relationships to support renal structure as an acceptable clinical trial surrogate endpoint for later renal functional deterioration
The second component examines the effects of age and gender at start of enzyme replacement therapy ERT as well as dosage levels of ERT on the renal cellular clearance of GL3 from Fabry patients by comparing baseline to follow-up kidney biopsies performed 5 11 and 60 months later with all comparisons matched for ERT treatment duration Our hypotheses for this component of the study are as follows
1 Enzyme Replacement TherapyERT instituted at younger ages is more effective in reducing podocytesPCdistal tubular cellsDTCand arterial smooth muscle cells ASMCGL-3 than in older Fabry patients
2 Earlier institution of ERT will stabilize PC numbers while later ERT institution especially in proteinuric adults may not prevent progressive decline in PC numbers and associated glomerular sclerosis tubulointerstitial injury and GFR loss
3 Whereas lower ERT dose may effectively clear GL-3 from endothelial and mesangial cells it will be less effective in clearing GL-3 from PC and also from DTC and ASMC
4 Affected cells will be cleared of GL-3 equivalently in females and males
Detailed Description:
Fabry disease is a rare genetic disease with deficient activity of enzyme alpha-galactosidase A Deficient activity of this enzyme leads to the accumulation of lipid-derived inclusions in different organs including kidney heart and vessels These inclusions can be found in the kidney even before birth The earliest known clinical manifestation of Fabry kidney disease is the appearance of excess protein in the urine which usually occurs in the second decade of life However our studies as well as those of other investigators show evidence that kidney injury starts much earlier Once excess protein is found in the urine kidney function deterioration becomes progressive and most Fabry patients require kidney transplantation or hemodialysis in the third to fifth decade of life The lesion or composite of lesions responsible for functional deterioration of the kidney in Fabry disease are not well known Their delineation using quantitative unbiased morphometric methods will help to understand this disease and to develop surrogate structural outcomes for early intervention trials Enzyme replacement therapy may stabilize kidney function However its long-term effect on kidney survival is not known Moreover there is no early known predictor of kidney dysfunction to adjust and evaluate effectiveness of enzyme replacement therapy Our studies of renal GL-3 clearance comparing pre-and post-ERT renal biopsies using the above methods will allow us to determine whether age at institution of treatment and ERT dose affect ERT induced GL-3 cellular clearance especially from those cells where ERT is less effective ie podocytes vascular smooth muscle cells and distal tubular cells Finally it is our hypothesis that mosaicism in Fabry disease females is such that cells such as podocytes are either affected or normal and that ERT clearance in the affected podocytes in females will as in males be dependant on age of institution of treatment and ERT dose
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| U54NS065768 | NIH | None | httpsreporternihgovquickSearchU54NS065768 |